The endogenous opioid peptide, beta-endorphin, is present in the brain in neurons of the hypothalamic arcuate nucleus. The aim of the present application is to test whether a subset of endorphinergic neurons that project from the arcuate nucleus to the dorsal medullary nucleus of the solitary tract (NTS) is involved in cardiovascular regulation. Specifically, the first hypothesis to be tested is that these neurons may be activated by antihypertensive drugs acting at alpha2-adrenergic receptors in the arcuate nucleus, and that the resulting release of beta- endorphin and subsequent activation of opiate receptors in the NTS contributes to the hypotensive, bradycardic and baroreflex facilitatory effects of these drugs (e.g. alpha-methyldopa, clonidine). The second hypothesis to be tested is that the same endorphinergic neurons may be also involved in mediating the hypotension elicited by endotoxin treatment, as suggested by remarkable similarities between the opioid component in the hypotension induced by centrally acting alpha2-receptor agonists and in the hypotension associated with various forms of shock, including endotoxic shock. The experiments proposed will combine neuropharmacological and molecular biological approaches for testing these hypotheses in rats. In the first type of experiments we will examine whether alpha2-receptor agonists microinjected into the arcuate nucleus cause hypotension and bradycardia inhibited by alpha2-receptor antagonists injected into the same site. Furthermore, will test whether these effects, as well as the hypotension elicited by endotoxin treatment, can be inhibited by opiate antagonists or beta-endorphin antiserum microinjected into the ipsilateral NTS, or by surgical deafferentation of the NTS. The second type of experiment will explore the effects of chronic treatment of rats with alpha2-receptor agonists with and without antagonists, as well as chronic treatment with endotoxin, on the gene expression of the precursor of beta-endorphin, proopiomelanocortin (POMC), in the arcuate nucleus and its subregions. The level of neuropeptide mRNA in a neuron is considered a good indicator of the physiological activity of that neuron. The proposed experiments could provide new insight into mechanisms of antihypertensive drug action and into the mechanism of endogenous opioid involvement in the cardiovascular changes associated with certain forms of shock.